Prostate cancer is the most common cancer of men in the United States with approximately 189,000 new cases and 30,000 deaths in 2002. Recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress. Prostate cancer is largely resistant to conventional chemotherapy, and currently there is no effective treatment for advanced, metastatic disease. Thus, there is an urgent need for therapies for advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-characterized glyeoprotein whose expression is largely restricted to prostate epithelial cells. In normal prostate, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. In prostate cancer, however, PSMA is expressed as a type II membrane protein with a large extraeellular domain. PSMA expression increases approximately 1000-fold with disease progression. PSMA also possesses carboxypeptidase activities that may play a role in metastasis. For these reasons, PSMA represents a highly attractive target for immunotherapy of prostate cancer. In the Phase I project, we generated and characterized a novel panel of fully human monoclonal antibodies (MAbs) that recognize PSMA on the surface of human prostate tumor cells. After a rigorous analysis of the MAbs, we have selected a lead candidate (termed "PSMAb") to advance into clinical development. PSMAb specifically recognizes a conformational epitope of human PSMA with subnamolar affinity. Importantly, radiolabeled forms of PSMAb can selectively target and potently kill PSMA-expressing tumor cells both in vitro and in vivo. The overall goal of this Phase II project is to advance PSMAb into human clinical testing. To this end, we will optimize our lead radiolabeled PSMAb construct for potency and specificity in vitro and in the best available animal models of human prostate cancer in parallel with the development and implementation of methods for producing clinical-grade antibody. Following completion of toxicology and additional IND-enabling studies, we will commence a Phase 1 human clinical trial designed to evaluate the safety and targeting of PSMAb in hormone-refractory prostate cancer. Successin the Phase II project is defined as the introduction of a promising new molecularly targeted therapy into clinical testing for a currently untreatable form of advanced prostate cancer.